Efforts to develop effective measures for the treatment of stroke have generally been based on the implicit assumption that one, or at the most several, factors control the progressive brain injury that occurs during the early hours of focal brain ischemia. Postischemic progression of brain damage appears to be extremely multifactorial. There is a finite probability that the assumption underlying most therapeutic stroke trials that seek to identify a dominant or controlling factor that determines post-ischemic progression of brain damage is incompatible with the fundamental nature of the problem. Postischemic progression of brain damage may be the result of a constellation of minor causes and the quest for a dominant or controlling cause would then be ultimately futile. Unconventional approaches may be required to arrest cellular destruction in brain ischemia. This project continues to investigate mammalian hibernation, a state of natural tolerance to severely reduced blood flow and oxygen delivery. Efforts to isolate and identify the factor or factors that regulate the controlled metabolic depression and tolerance of profound brain ischemia that forms the essence of natural hibernation are in progress. Such factors with pleiotropic effects may have benefit in the treatment of progressive brain damage in human stroke that is characterized by loss of homeostatic control due to activation of a multitude of pathophysiological postischemic events. The existence of regulatory factors in hibernation is supported by several findings that render passive submission to the effect of ambient temperature unlikely: (1) The onset and rate of development of bradycardia and reduced oxygen consumption during the transition to hibernation is rapid and precedes a more gradual drop in body temperature. (2) Regulation of enzyme function and gene expression that contributes to preservation of homeostasis during hibernation has been demonstrated. (3) Artificially induced hypothermia leads to rapid death in animals otherwise able to tolerate the same degree of hypothermia during natural hibernation. The identification of these putative control mechanisms may enable us to prevent or minimize the breakdown of homeostasis and cellular damage in cerebral ischemia in other species.